JP3239506B2 - Heterocyclic derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to novel heterocyclic derivatives and their pharmaceutically acceptable salts.
More specifically, the present invention relates to a novel imidazole derivative having a pharmacological activity such as angiotensin II antagonism and the like, a pharmaceutically acceptable salt thereof, a method for producing the same, and a pharmaceutical composition comprising the derivative or a salt thereof. And the use of the derivatives and salts thereof as medicaments.

Accordingly, one object of the present invention is to provide novel imidazole derivatives useful as potent and selective antagonists of the angiotensin II receptor and pharmaceutically acceptable salts thereof.

[0003] Another object of the present invention is to provide a method for producing the above imidazole derivative or a salt thereof.

[0004] It is a further object of the present invention to provide a pharmaceutical composition comprising the above imidazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

Still another object of the present invention is to provide angiotensin II useful for treating or preventing angiotensin II-mediated diseases in humans or animals, such as hypertension (eg, essential hypertension, renal hypertension, etc.), heart failure and the like. II
An object of the present invention is to provide the use of the above imidazole derivative or a pharmaceutically acceptable salt thereof as a therapeutic agent such as an antagonist.

[0006]

The imidazole derivatives according to the invention are new and can be represented by the formula (I):

Embedded image (Wherein R ¹ is hydrogen, halogen, nitro, lower alkyl, lower alkoxy, amino or acylamino,
R ² , R ³ and R ⁴ are each hydrogen, halogen, nitro, cyano, lower alkyl, lower alkenyl, lower alkylthio, mono-, di- or trihalo (lower) alkyl, oxo (lower) alkyl, hydroxy (lower) alkyl Or optionally esterified carboxy or R ² and R ³ are linked together to form 1,3-butadienylene, R ⁵ is hydrogen or imino protecting group, R ⁶ and R ⁷ are hydrogen or lower, respectively. Alkyl, R ⁸ is hydrogen or lower alkyl optionally having halogen or lower alkoxy, A is lower alkylene, Q is CH or N, X is N or CH, Y is NH, O or S, Z is N
H, S, SO ₂ or O).

According to the present invention, the target compound (I) can be produced by the following method.

Manufacturing method 1

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Manufacturing method 2

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Manufacturing method 3

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Production method 4

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Embedded image (Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ ,
A, Q, X, Y and Z are each as defined, R ⁴ _a is oxo (lower) alkyl or halogen, R
⁴ _b is hydroxy (lower) alkyl or hydrogen, R ⁵ _a is an imino protecting group, and R ⁹ is an acid residue).

Suitable salts of the compounds (I) are the customary non-toxic pharmaceutically acceptable salts and include, for example, salts with bases or acid addition salts, for example salts with inorganic bases, such as alkali metal salts. Salts (eg, sodium salt, potassium salt, cesium salt, etc.), alkaline earth metal salts (eg, calcium salt, magnesium salt, etc.), ammonium salts; salts with organic bases, eg, organic amine salts (eg, triethylamine salt) Pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N, N-dibenzylethylenediamine salts and the like); inorganic acid addition salts (eg, hydrochloride, hydrobromide, sulfate,
Phosphates and the like); organic carboxylic acid or sulfonic acid addition salts (eg, formate, acetate, trifluoroacetate,
Maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.); salts with basic or acidic amino acids (eg, arginine, aspartic acid, glutamic acid, etc.); Preferred examples are acid addition salts.

In the foregoing and following description of this specification, suitable examples and explanations of the various definitions included within the scope of the present invention are described in detail below.

"Lower" means 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise indicated.

Suitable lower alkyl and lower alkyl moieties in "lower alkylthio" include straight-chain or branched alkyl having 1 to 6 carbon atoms, for example,
Methyl, ethyl, propyl, isopropyl, butyl, t
-Butyl, pentyl, hexyl, and among them, preferred are alkyl having 1 to 5 carbon atoms.

Suitable "lower alkenyl" include vinyl, 1-propenyl, allyl, 1-butenyl, 2-pentenyl and the like, of which those having 2 to 4 carbon atoms are preferred. And most preferred is vinyl.

Suitable "lower alkylene" includes 1 to 6 carbon atoms such as methylene, ethylene, trimethylene, propylene, tetramethylene, methyltrimethylene, dimethylethylene, hexamethylene, etc. Preferred is methylene.

Suitable "halogens" include fluorine, chlorine, bromine and iodine.

Suitable "lower alkoxy" include straight or branched chain alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy and the like. Preferred among them is C
₁ -C ₄ alkoxy and the like.

Suitable acyl moieties in "acylamino" include carbamoyl, thiocarbamoyl, sulfamoyl, aliphatic acyl, aromatic acyl, heterocyclic acyl, among which lower alkanoyl is preferred. (Eg, formyl, acetyl, propionyl, hexanoyl, etc.).

Suitable "mono-, di- or trihalo (lower) alkyl" include chloromethyl, fluoromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trifluoromethylpropyl and the like.

Suitable "hydroxy (lower) alkyl" includes hydroxymethyl, hydroxyethyl and the like.

Suitable "oxo (lower) alkyl" includes formyl, formylmethyl, formylethyl and the like.

Suitable "esterified carboxy" includes lower alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.).

Suitable "imino protecting groups" include conventional ones, and preferred examples include alk (lower) such as mono- (or di- or tri-) phenyl- (lower) alkyl. Alkyl (eg, benzyl, benzhydryl, trityl, etc.), acyl (eg, tert-butoxycarbonyl, etc.), lower alkanesulfonyl (eg,
Mesyl etc.), Allensulfonyl (eg Tosyl etc.)
And the most preferred of them is trityl.

Suitable "acid residues" include halogen (eg, fluorine, chlorine, bromine, iodine), acyloxy (eg, acetoxy, tosyloxy, mesyloxy, etc.).

A preferred embodiment of the heterocyclic derivative (I) of the present invention can be represented by the following formula:

Embedded image Wherein A is lower alkylene, R ² , R ³ and R ⁴ are each hydrogen, halogen or nitro, or R ² and R ³ are bonded together to form 1,3-butadienylene, and R ⁶ is lower alkyl. , R ⁷ and R ⁸ are each hydrogen or lower alkyl, Z is NH, S, SO ₂ or O, wherein lower alkyl, lower alkylene and halogen have the same meanings as before.

Further, a preferred embodiment of the compound (I) can be represented by the following formula.

Embedded image (Wherein R ¹ is hydrogen, halogen, nitro, lower alkoxy, amino or acylamino, A is lower alkylene,
Q is CH or N, R ² , R ³ and R ⁴ are each hydrogen, halogen or nitro, or R ² and R ³ are bonded together to form 1,3-butadienylene, and R ⁶ is lower alkyl. , R ⁷ and R ⁸ are each hydrogen or lower alkyl, Z is NH, S, SO ₂ or O, wherein lower alkyl, halogen, lower alkoxy, acylamino and lower alkylene have the same meanings as before. .

Further, a preferred embodiment of the compound (I) can be represented by the following formula.

Embedded image (Wherein R ¹ is hydrogen, halogen, nitro, lower alkyl, lower alkoxy, amino or acylamino,
R ^2, R ³ and R ⁴ each represents hydrogen, halogen, nitro, cyano, or whether a lower alkyl or lower alkenyl R ² and R ³ are bonded to form a 1,3-butadienylene together, R ⁶ is Lower alkyl, R ⁷ and R ⁸ are each hydrogen or lower alkyl, A is lower alkylene,
Q represents CH or N, and Z represents NH, S, SO ₂ or O).

Further, a preferred embodiment of the compound (I) can be represented by the following formula.

Embedded image (Wherein R ¹ is hydrogen, halogen, nitro, lower alkyl, lower alkoxy, amino or acylamino,
R ² , R ³ and R ⁴ are each hydrogen, halogen, nitro, cyano, lower alkyl, lower alkenyl, lower alkylthio, mono-, di- or trihalo (lower) alkyl, oxo (lower) alkyl or hydroxy (lower) alkyl Or optionally esterified carboxy or R ² and R ³ are linked together to form 1,3-butadienylene, R ⁶ and R ⁷ are each hydrogen or lower alkyl, R ⁸ is hydrogen or halogen or Lower alkyl optionally having lower alkoxy, A is lower alkylene, Q is CH or N, and Z is NH, S,
Means SO ₂ or O).

Further, a preferred embodiment of the compound (I) can be represented by the following formula.

Embedded image (Wherein R ¹ is hydrogen, halogen, nitro, lower alkyl, lower alkoxy, amino or acylamino,
R ² , R ³ and R ⁴ are each hydrogen, halogen, nitro, cyano, lower alkyl, lower alkenyl, lower alkylthio, mono-, di- or trihalo (lower) alkyl, oxo (lower) alkyl, hydroxy (lower) alkyl Or optionally esterified carboxy or R ² and R ³ are linked together to form 1,3-butadienylene, R ⁵ is a hydrogen or imino protecting group, R ⁶ and R ⁷ are each hydrogen or lower. Alkyl, R ⁸ is hydrogen or lower alkyl optionally having halogen or lower alkoxy, A is lower alkylene, Q is CH or N, and Z means NH, S, SO ₂ or O).

Further, a preferred embodiment of the compound (I) can be represented by the following formula.

Embedded image (Wherein R ¹ is hydrogen, halogen, nitro, lower alkyl, lower alkoxy, amino or acylamino, R ²
And R ³ are each hydrogen, halogen, nitro, cyano, lower alkyl or lower alkenyl, or R ² and R ³ are linked together to form 1,3-butadienylene, and R ⁶ and R ⁷ are each hydrogen Or lower alkyl, R ⁸ is hydrogen or lower alkyl optionally having halogen or lower alkoxy, A is lower alkylene, Q is CH or N, and Z means NH, S, SO ₂ or O).

In particular, preferred compounds (I) of the present invention can be represented by the following formula:

Embedded image (Wherein R ² , R ³ and R ⁴ are each hydrogen, halogen, nitro, cyano, lower alkyl, lower alkenyl,
Lower alkylthio, mono-, di- or trihalo (lower) alkyl, oxo (lower) alkyl, hydroxy (lower) alkyl or optionally esterified carboxy (more preferably carboxy or lower alkoxycarbonyl) or R ² and R ³ is linked together to form 1,3-butadienylene, R ⁶ and R ⁷ are each hydrogen or lower alkyl, R ⁸ is hydrogen or lower alkyl optionally having halogen or lower alkoxy, Y is NH, O or S, and Z is NH, S, S
O ₂ or means O). And furthermore, the expression

Embedded image A more preferred embodiment of the group is represented by the formula:

[0034]

Embedded image (Wherein, R ² _a is hydrogen, halogen, cyano, lower alkyl or lower alkylthio, R ³ _a is hydrogen, halogen, nitro, lower alkyl, lower alkenyl, trihalo (lower)
Alkyl, oxo (lower) alkyl, hydroxy (lower) alkyl or lower alkoxycarbonyl),

[0035]

Embedded image (Wherein R ² _b and R ³ _b each represent halogen),

Embedded image Wherein R ² _c is hydrogen, halogen or lower alkyl,
³ _c represents lower alkyl, R ⁴ _c represents hydrogen or halogen),

[0036]

Embedded image Wherein R ² _d represents hydrogen, halogen or lower alkyl, and R ³ _d represents lower alkyl),

Embedded image (Wherein R ² e represents hydrogen or halogen), or

[0037]

Embedded image And the most preferred are:

Embedded image (Wherein R ² _f and R ³ _f each represent hydrogen, lower alkyl or halogen).

The method for producing the target compound (I) of the present invention will be described in detail below. Production method 1 : Target compound (I) or a salt thereof is compound (I)
It can be produced by subjecting I) to a reaction for forming a tetrazole group. This reaction is carried out by a conventional reaction capable of converting a cyano group such as a metal azide into a tetrazolyl group, for example, an alkali metal azide (for example, potassium azide, sodium azide, etc.), triazide (lower)
The reaction is performed in the presence of a reagent such as an alkyl tin (for example, trimethyltin azide and the like) and a triaryltin azide (for example, triphenyltin azide and the like). This reaction is usually
The reaction is performed in the presence of a base such as tri (lower) alkylamine (eg, triethylamine and the like) or 1,3-dimethyl-2-imidazolidinone. The reaction is usually performed in a solvent such as xylene, dioxane, chloroform, methylene chloride, 1,2-dichloroethane, tetrahydrofuran, pyridine, acetonitrile, dimethylformamide or any other solvent that does not adversely affect the reaction . The reaction temperature is not particularly limited, and the reaction is usually carried out under heating or heating, preferably under heating. Furthermore,
Compound (I) wherein R ¹ is amino can be prepared by reducing the corresponding nitro compound in a conventional manner, and compound (I) wherein R ¹ is acylamino is obtained by converting the amino compound obtained above to It can be produced by acylation by a conventional method. Furthermore, within the scope of this reaction are also mentioned the cases in which the dihalo (lower) alkyl radical of R ² , R ³ or R ⁴ is converted into an oxo (lower) alkyl radical during the reaction or in the aftertreatment stage of the process. Can be

Production method 2 : The target compound (Ib) or a salt thereof can be produced by reducing the compound (Ia) or a salt thereof. The reduction includes, for example, chemical reduction with an alkali metal borohydride (eg, sodium borohydride, etc.) and catalytic reduction with a palladium catalyst (eg, palladium carbon, etc.). This reaction is usually carried out in a conventional solvent that does not adversely affect the reaction, such as alcohol (eg, methanol, ethanol, propanol, etc.), tetrahydrofuran, dioxane, dimethylsulfoxide, N, N-dimethylformamide or a mixture thereof. Done in

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling to heating.

Production method 3 : The desired compound (I) or a salt thereof can be produced by reacting the compound (III) or a salt thereof with the compound (IV) or a salt thereof. This reaction is usually carried out with an alkyl lithium (eg, n-
Butyllithium, etc.), alkali metal hydrides (for example,
Sodium hydride, potassium hydride, etc.), di (lower) alkylamines (eg, diisopropylamine), tri (lower) alkylamines (eg, trimethylamine, triethylamine, etc.), pyridine or derivatives thereof (eg, picoline, lutidine, The reaction is carried out in the presence of a base such as 4-dimethylaminopyridine. The reaction is usually performed in a solvent such as dioxane, dimethylsulfoxide, dimethylformamide, diethylformamide, dimethylacetamide, benzene, tetrahydrofuran or any other solvent that does not adversely affect the reaction. If the base used is a liquid, it can also be used as a solvent. The reaction temperature is not particularly limited, and is usually performed under cooling, at room temperature, or under heating.

Production method 4 : The desired compound (Id) or a salt thereof can be produced by subjecting the compound (Ic) or a salt thereof to a reaction for removing an imino protecting group. Suitable methods for removing the imino protecting group include conventional methods capable of removing the imino protecting group for the tetrazolyl group, such as hydrolysis, reduction and the like. The hydrolysis is preferably performed in the presence of a base or an acid. Suitable bases include, for example, alkali metal hydroxides (eg, sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (eg, magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonates (Eg, sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonates (eg, magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonates (eg, sodium bicarbonate, potassium bicarbonate, etc.), alkali metal acetates (Eg, sodium acetate, potassium acetate, etc.), alkaline earth metal phosphates (eg, magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphates (eg, disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.) ) And trialkylamines (eg, trimethylamido). , Triethylamine), picoline, N- methylpyrrolidine, N- methylmorpholine, 1,5-diazabicyclo [4.3.0] nonane-5-one, 1,4
Organic bases such as diazabicyclo [2.2.2] octane, 1,5-diazabicyclo [5.4.0] undecene-5 and the like can be mentioned. Hydrolysis using a base is often carried out in water or in a hydrophilic organic solvent or a mixture thereof. Suitable acids include organic acids (eg, formic acid, acetic acid, propionic acid, etc.) and inorganic acids (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, etc.). It is performed in a mixed solvent. The reaction temperature is not particularly limited, and is usually performed at room temperature or under heating or heating.

The starting compounds (II), (III) and (IV) are new and can be prepared by the following preparations or by methods analogous thereto or by customary methods.

The objective compound (I) of the present invention can be isolated and purified by a conventional method such as extraction, precipitation, fractional crystallization, recrystallization, chromatography and the like.

The target compound (I) thus obtained
Can be converted to its salt in a conventional manner.

The compound (I) of the present invention exhibits angiotensin antagonism such as vasodilatory activity, is useful as an angiotensin II antagonist and has high blood pressure (eg, essential hypertension, renal hypertension, etc.), It is effective for various angiotensin II-mediated diseases such as heart failure.

Further, the compound of interest of the present invention can be used for heart disease (eg, angina, arrhythmia, myocardial infarction, etc.), hyperaldosteronism, cerebrovascular disease, senile dementia, eye disease (eg,
It is useful as a therapeutic and / or prophylactic agent for glaucoma and the like, and as a diagnostic substance for testing the renin-angiotensin system.

For therapeutic or prophylactic administration, the compound of interest (I) of the present invention may be a pharmaceutically acceptable organic or inorganic solid or liquid excipient suitable for oral, parenteral, topical and inhalational administration. It is used in the form of conventional pharmaceutical preparations containing the compounds as active ingredients in a mixture with carriers. The pharmaceutical preparation can be in solid form, such as tablets, granules, powders, capsules, or in liquid form, such as solutions, suspensions, syrups, emulsions, lemonades, and the like.

If necessary, auxiliaries, stabilizers, wetting agents and other commonly used additives, such as lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, clay, sucrose, corn starch , Talc, gelatin, agar, pectin, peanut oil, olive oil, cocoa butter, ethylene glycol and the like can be included in the above formulation.

The dosage of compound (I) will vary and also depends on the age, the condition of the patient, the type of disease or condition, the type of compound (I) to be applied and the like. Generally, an amount between 0.01 mg and about 500 mg or more per day can be administered to the patient. The compound of interest (I) of the present invention is used in the treatment of disease at an average dose of about 0.05 mg, 0.1 mg, 0.25 mg, 0.5 m
g, 1 mg, 20 mg, 50 mg, and 100 mg may be used.

[0051]

The present invention will be described in more detail with reference to the following production examples and examples. Production Example 1 2-ethylthio-7-methyl-3H-imidazo [4.5
-B] pyridine (1.50 g) in dimethylformamide (15
ml) solution was added sodium hydride (341 mg) at room temperature under a nitrogen atmosphere. The mixture is allowed to stand at the same
Stirred for minutes. 1- (4-Bromomethylphenyl) -4-chloropyrrol-2-carbonitrile (2.19
g) in dimethylformamide (15 ml) was added. The mixture was stirred at room temperature for 3 hours. The mixture was treated with aqueous sodium bicarbonate and extracted twice with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1/1).
Eluting with), 2-ethylthio-3- [4- (4-chloro-
2-cyano-1-pyrrolyl) benzyl] -7-methyl-
3H-imidazo [4,5-b] pyridine (850 mg) was obtained as a yellow oil. NMR (CDCl ₃ , δ): 1.46 (3H, t, J = 7.5Hz), 2.64 (3H, s),
3.41 (2H, q, J = 7.5Hz), 5.44 (2H, s), 6.89 (1H, d, J = 2Hz),
6.96-7.04 (2H, m), 7.35 (2H, d, J = 9Hz), 7.46 (2H, d, J = 9H
z), 8.14 (1H, d, J = 5Hz)

Production Example 2 2-ethylthio-7-methyl-3H-imidazo [4.5
-B] -Pyridine (3.00 g) in dimethylformamide (30 ml) was added little by little at 10 ° C or lower while cooling with ice under a nitrogen atmosphere under a nitrogen atmosphere. To the reaction mixture was added a solution of 3- (4-bromomethylphenyl) -2-bromopyrrole-4-carbonitrile (5.50 g) in dimethylformamide (50 ml) at the same temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 3 hours. The resulting mixture was extracted twice with ethyl acetate. The extract was washed with water, dried, and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluted with a mixture of ethyl acetate and n-hexane (1: 1)) to give 3- [4- (2-bromo-4-cyano-1-methyl-2-pyrrolyl). ) Benzyl] -2-ethylthio-7-
Methyl-3H-imidazo [4,5-b] pyridine (1.32
g) was obtained as a white powder. mp: 161-163 ° C NMR (CDCl ₃ , δ): 1.45 (3H, t, J = 7.5Hz), 2.65 (3H, s),
3.39 (2H, q, J = 7.5Hz), 3.68 (3H, s), 5.43 (2H, s), 6.99 (1
H, d, J = 5Hz), 7.30 (1H, s), 7.37 (2H, d, J = 9Hz), 7.48 (2H,
d, J = 9Hz), 8.15 (1H, d, J = 5Hz)

Production Example 3 2-ethylthio-7-methyl-3H-imidazo [4.5
-B] -Pyridine (3.00 g) in dimethylformamide (30 ml) was slowly added with sodium hydride (627 mg) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour. 1-ethyl-2- (4-methanesulfonyloxymethylphenyl) -5-methylpyrrol- was added to the mixture.
A solution of 2-carbonitrile (4.94 g) in dimethylformamide (50 ml) was added. The reaction mixture was stirred at room temperature for 3 hours. Water was added to this and extracted twice with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by silica gel flash column chromatography (eluted with n-hexane / ethyl acetate (1/1)) to give 3- [4- (3-cyano-1-ethyl-5-methyl-2-pyrrolyl) benzyl ] -2-Ethylthio-7-methyl-3H-imidazo [4,5-b]
Pyridine (1.52 g) was obtained as a colorless oil. NMR (CDCl ₃ , δ): 1.26 (3H, t, J = 7.5Hz), 1.45 (3H, t, J =
7.5Hz), 2.29 (3H, s), 2.65 (3H, s), 3.40 (2H, q, J = 7.5Hz),
3.81 (2H, q, J = 7.5Hz), 5.46 (2H, s), 6.20 (1H, s), 7.00
(1H, d, J = 5Hz), 7.33 (2H, d, J = 9Hz), 7.40 (2H, d, J = 9Hz),
8.16 (1H, d, J = 5Hz)

Production Example 4 2-amino-4-methyl-3-nitropyridine (25.0
g) and N, N-dimethylaniline (50 ml)
C., acetyl chloride (12.2 ml) was added dropwise to the solution, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was extracted with ethyl acetate. The extract was washed with water (3 times) and brine. The solution was dried over magnesium sulfate and the solvent was distilled off under reduced pressure.
The residue was dissolved in methanol (200ml) and to this was added a saturated aqueous solution of sodium bicarbonate (50ml). The mixture was stirred at 70 ° C. for 30 minutes. After cooling to room temperature, the solvent was distilled off. The residue was extracted with ethyl acetate. The extract was washed with water. The aqueous layer was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The resulting crude crystals were suspended in diisopropyl ether (200ml) and the mixture was heated to 90 ° C. After allowing the mixture to cool to room temperature, the solid was collected by filtration and air dried at room temperature to give 2-acetylamino-4-methyl-2-nitropyridine (25.99 g) as pale yellow needles. Was. The filtrate was concentrated under reduced pressure to give a second crop (1.31).
g) was obtained. mp: 146-149 ° C NMR (CDCl ₃ , δ): 2.30 (3H, s), 2.51 (3H, s), 7.12 (1H,
d, J = 5Hz), 8.39 (1H, d, J = 5Hz), 8.45 (1H, br, s)

Production Example 5 To a solution of sodium hydride (3.2 g) in dimethylformamide (100 ml) was added 2-acetylamino-4-methyl-2-nitropyridine (15.21 g) little by little at 40 ° C. or lower. The mixture was stirred at room temperature for 30 minutes,
Then, 1- (4-methanesulfonyloxymethylphenyl) -5-methyl-2-carbonitrile (2
A solution of 2.65 g) in dimethylformamide (120 ml) was added dropwise. The reaction mixture was stirred at room temperature for 1.5 hours. The mixture was cooled with ice and saturated aqueous sodium bicarbonate was added. The mixture was extracted with ethyl acetate, the organic layer was separated and washed with brine. The aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted with n-hexane / ethyl acetate = 2/1 → 1/2) to give 2- [N-acetyl-4- [1- (2-cyano-
5-Methyl) pyrrolyl] benzyl] amino-4-methyl-3-nitropyridine (22.65 g) was obtained as a brown viscous oil. NMR (CDCl ₃ , δ): 1.99 (3H, s), 2.15 (3H, s), 2.44 (3H,
s), 4.75-5.33 (2H, m), 6.08 (1H, d, J = 5Hz), 6.86 (1H, d, J =
5Hz), 7.06-7.76 (5H, m), 8.50 (1H, d, J = 5Hz)

Production Example 6 2- [N-acetyl-4- [1- (2-cyano-5-methylpyrrolyl) benzyl)]-4-methyl-3-nitropyridine (20.34 g) in methanol (500 ml)
The methanol solution of sodium methoxide (2
(8% w / v; 50 ml) at room temperature. The mixture was stirred at the same temperature for 1 hour and then diluted with diethyl ether. The aqueous layer was extracted with diethyl ether, and the combined ether layers were washed with brine and dried over magnesium sulfate. After filtration, the organic layer was concentrated under reduced pressure. The residue was chromatographed on silica gel (eluted with dichloromethane-n-hexane (3: 1 then 4: 1)) to give 2- [4- [1- (2-cyano-5).
-Methyl) pyrrolyl] benzyl] amino-4-methyl-
3-Nitropyridine was obtained as a yellow solid. Recrystallization gave a yellow prism (17.18 g). mp: 102-103 ° C NMR (CDCl ₃ , δ): 2.14 (3H, s), 2.57 (3H, s), 4.86 (2H,
d, J = 8Hz), 6.05 (1H, d, J = 4Hz), 6.58 (1H, d, J = 5Hz), 6.84
(1H, d, J = 4Hz), 7.28 (2H, d, J = 9Hz), 7.47 (2H, d, J = 9Hz),
7.88 (1H, br, s), 8.16 (1H, d, J = 5Hz)

Production Example 7 2- [4- [1- (2-cyano-5-methyl) pyrrolyl] benzyl] amino-4-methyl-3-nitropyridine (500 mg), 10% palladium on carbon (50 mg)
And a mixture of ethanol (10 ml) was stirred at room temperature under a hydrogen atmosphere (1 atm) for 5 hours. 1,
4-Dioxane was added with stirring at the same temperature under a hydrogen atmosphere (1 atm). After 3 hours, an additional 10% palladium on carbon (100 mg) was added to the mixture and stirred at the same temperature under a hydrogen atmosphere (1 atm) for 105 minutes. Ethanol is added to the mixture, and the mixture is filtered through celite, and the solvent of the filtrate is evaporated under reduced pressure to give 3-amino-2- [4- [1- (2-cyano-5-methylpyrrolyl) benzyl. A crude product of [amino] -4-methylpyridine (537 mg) was obtained, which was used for the next reaction without further purification.

Production Example 8 3-Amino-2- [4- [1- (2-cyano-5-methylpyrrolyl) benzyl] amino] -4-methylpyridine (530 mg) and tetraethyl orthocarbonate (3
(31 μl) in acetic acid (5 ml) was stirred at room temperature for 4.5 hours. Tetraethyl orthocarbonate (331μ)
After further addition of 1), the mixture was stirred at room temperature for 1 hour and then at 70 ° C. for 2 hours. The solvent was removed under reduced pressure and the residue was extracted with ethyl acetate, the extract was washed with saturated sodium bicarbonate, water (twice) and brine, and dried over magnesium sulfate. After filtration, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate-n-hexane (1: 1).
3, then 1: 4)), 3- [4-1-
(2-cyano-5-methyl) pyrrolyl] benzyl] -2
-Ethoxy-7-methyl-3H-imidazo [4,5-
b] Pyridine (429 mg) was obtained as a pink amorphous solid. NMR (CDCl ₃ , δ): 1.47 (3H, t, J = 7.5Hz), 2.10 (3H, s),
2.56 (3H, s), 4.65 (2H, q, J = 7.5Hz), 5.32 (2H, s), 6.04 (1
H, d, J = 4Hz), 6.85 (1H, d, J = 4Hz), 6.95 (1H, d, J = 5Hz), 7.
22 (2H, d, J = 9Hz), 7.45 (2H, d, J = 9Hz), 8.06 (1H, d, J = 5Hz)

Production Example 9 2-amino-4,6-dimethyl-3-nitropyridine (1
A mixture of 4.91 g) and N, N-dimethylaniline (80 ml) was heated to 70 ° C. Acetyl chloride was added dropwise to this solution at 70 ° C., and the mixture was stirred at 70 ° C. for 2.5 hours. Ethyl acetate (500 ml) was added to the reaction mixture. The organic layer was separated and washed with water (3 times) and brine. The solution was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was dissolved in hot diisopropyl ether (200ml) and cooled to room temperature. After the mixture was cooled in an ice bath for 1 hour, the solid collected by filtration was washed with cold diisopropyl ether, purified by silica gel flash column chromatography (a mixture of ethyl acetate and n-hexane (1 : 9, then 2:
1)) to give a brown oil, which was dissolved in methanol (40 ml). To this solution was added saturated sodium bicarbonate (10 ml) and stirred at room temperature for 70 minutes.
The mixture was diluted with ethyl acetate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, dried over magnesium sulfate and concentrated under reduced pressure. Diisopropyl ether (50
ml) was added. After cooling, the solid was collected by filtration and washed with diisopropyl ether to give 2-acetylamino-4,6-dimethyl-3-nitropyridine (5.56 g) as a colorless powder. NMR (CDCl ₃ , δ): 2.28 (3H, s), 2.44 (3H, s), 2.50 (3H,
s), 6.94 (1H, s), 8.30 (1H, br, s)

Preparation Example 10 To a solution of 2-acetylamino-4,6-dimethyl-2-nitropyridine (330 mg) in dimethylformamide (3 ml) was added sodium hydride (64 mg) at room temperature. The mixture was stirred at room temperature for 30 minutes, and to this was added dropwise a solution of 1- (4-methanesulfonyloxymethylphenyl) -1-ethyl-5-methyl-2-carbonitrile (500 mg) in dimethylformamide (6 ml). Added. The reaction mixture was stirred at room temperature for 30 minutes. The mixture was cooled with saturated ammonium chloride and extracted with ethyl acetate. The extract was washed with water and brine and dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted with ethyl acetate / n-hexane = 1/1 → 2/1) to give 2- [N-acetyl-4- [2- (3-cyano-1-ethyl- 5-Methyl) pyrrolyl] benzyl] amino-4,6-dimethyl-3-nitropyridine (514 mg) was obtained as a brown viscous oil. NMR (CDCl ₃ , δ): 1.17 (3H, t, J = 7.5Hz), 1.97 (3H, br,
s), 2.25 (3H, s), 2.33 (br, s, 3H), 2.53 (3H, s), 3.84 (2H,
q, J = 7.5Hz), 4.73-5.36 (2H, m), 6.19 (1H, s), 7.04-7.86
(5H, m)

Production Example 11 The following compound was obtained in the same manner as in Production Example 6. 2- [4-
[2- (3-Cyano-1-ethyl-5-methyl) pyrrolyl] benzyl] amino-4,6-dimethyl-3-nitropyridine. mp: 122-126 ° C NMR (CDCl ₃ , δ): 1.20 (3H, t, J = 7.5Hz), 2.30 (3H, s),
2.40 (3H, s), 2.55 (3H, s), 3.86 (2H, q, J = 7.5Hz), 4.87 (2
H, d, J = 5Hz), 6.21 (1H, s), 6.40 (1H, s), 7.37 (2H, d, J = 9H
z), 7.46 (2H, d, J = 9Hz), 8.21 (1H, br, t, J = 5Hz)

Production Example 12 The following compound was obtained in the same manner as in Production Example 7, and this compound was used without further purification in the next reaction. 3-Amino-2- [4- [2- (3-cyano-1-ethyl-5-methyl) pyrrolyl] benzyl] amino-4,6-dimethylpyridine.

Production Example 13 The following compound was obtained in the same manner as in Production Example 8. 3- [4-
[2- (3-cyano-1-ethyl-5-methyl) pyrrolyl] benzyl] -5,7-dimethyl-2-ethoxy-3
H-imidazo [4,5-b] pyridine. NMR (CDCl ₃ , δ): 1.15 (3H, t, J = 7.5Hz), 1.42 (3H, t, J =
7.5Hz), 2.29 (3H, s), 2.50 (3H, s), 2.56 (3H, s), 3.83 (2
(H, q, J = 7.5Hz), 4.61 (2H, q, J = 7.5Hz), 5.28 (2H, s), 6.20
(1H, s), 6.82 (1H, s), 7.31 (2H, d, J = 9Hz), 7.41 (2H, d, J =
9Hz)

Production Example 14 3-Amino-2- [4- [2- (3-cyano-1-ethyl-5-methyl) pyrrolyl] benzyl] amino-4,6
A mixture of -dimethylpyridine (0.50 mmol) and 1,1'-carbonyldiimidazole (97 mg) was stirred at room temperature for 1/2 hour and then heated at reflux for 12 hours, during which time 1,
Additional 1'-carbonyldiimidazole (65 mg) was added. After cooling, the mixture was extracted with ethyl acetate and 1N
Washed with hydrochloric acid, water and saturated saline. After drying over magnesium sulfate, the solvent is distilled off under reduced pressure and the residue is recrystallized from ethanol to give 3- [4- [2- (3-cyano-1-ethyl-5-methyl) pyrrolyl] benzyl ]-
5,7-Dimethyl-2-hydroxy-3H-imidazo [4,5-b] pyridine (120 mg) was obtained as a pale orange powder. mp: 281-286 ° C NMR (CDCl ₃ , δ): 1.15 (3H, t, J = 7.5Hz), 2.27 (3H, s),
2.34 (3H, s), 2.50 (3H, s), 3.32 (2H, q, J = 7.5Hz), 5.20 (2H
H, s), 6.19 (1H, s), 6.70 (1H, s), 7.31 (2H, d, J = 9Hz), 7.5
6 (2H, d, J = 9Hz), 9.85 (1H, s)

Production Example 15 3- [4- [2- (3-cyano-1-ethyl-5-methyl) pyrrolyl] benzyl] -5,7-dimethyl-2-hydroxy-3H-imidazo [4,5- b] pyridine (120
mg) and N, N-dimethylaniline (80 μl) in phosphorus oxychloride (0.9 ml) were refluxed for 2.5 hours. The solvent was removed under reduced pressure and the remaining solvent was azeotroped off with toluene. The residue was extracted with ethyl acetate and the extract was washed with saturated sodium bicarbonate and saturated saline, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 2-chloro-3- [4- [2- ( 3-cyano-1-ethyl-5-methyl) pyrrolyl] benzyl]-
5,7-Dimethyl-3H-imidazo [4,5-b] pyridine was obtained as a yellow amorphous solid. NMR (CDCl ₃ , δ): 1.17 (3H, t, J = 7.5Hz), 2.28 (3H, s),
2.60 (3H, s), 2.64 (3H, s), 3.82 (2H, q, J = 7.5Hz), 5.51 (2
H, s), 6.20 (1H, s), 6.97 (1H, s), 7.36 (2H, d, J = 9Hz), 7.4
3 (2H, d, J = 9Hz)

Preparation Example 16 2-chloro-3- [4- [2- (3-cyano-1-ethyl-5-methyl) pyrrolyl] benzyl] -5,7-dimethyl-3H-imidazo [4,5- b] pyridine (120 mg)
To a suspension of in methanol (1 ml) was added sodium methoxide (28% w / v in methanol; 0.57 ml) and tetrahydrofuran (1 ml) at room temperature. After the mixture became a clear solution, it was heated at 50 ° C. for 7 hours. The mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate and saturated saline. The organic layer was dried over magnesium sulfate, filtered, and evaporated under reduced pressure to give 3-
[4- [2- (3-cyano-1-ethyl-5-methyl)
Pyrrolyl] benzyl] -5,7-dimethyl-2-methoxy-3H-imidazo [4,5-b] pyridine was obtained as a pale brown viscous oil (101 mg). NMR (CDCl ₃ , δ): 1.16 (3H, t, J = 7.5Hz), 2.27 (3H, s),
2.53 (3H, s), 2.59 (3H, s), 3.33 (2H, q, J = 7.5Hz), 4.20 (3
H, s), 5.29 (2H, s), 6.20 (1H, s), 6.83 (1H, s), 7.33 (2H,
d, J = 9Hz), 7.40 (2H, d, J = 9Hz)

Production Example 17 The following compound was obtained in the same manner as in Production Example 16. 3- [4-
[2- (3-cyano-1-ethyl-2-methyl) pyrrolyl] benzyl-5,7-dimethyl-2-propoxy-3
H-imidazo [4,5-b] pyridine. mp: 133-137 ° C NMR (CDCl ₃ , δ): 0.97 (3H, t, J = 7.5Hz), 1.15 (3H, t, J =
7.5Hz), 1.81 (2H, m), 2.26 (3H, s), 2.50 (3H, s), 2.57 (3H
H, s), 3.82 (2H, q, J = 7.5Hz), 4.50 (2H, t, J = 8Hz), 5.39 (2
H, s), 6.20 (1H, s), 6.80 (1H, s), 7.32 (2H, d, J = 9Hz), 7.
41 (2H, d, J = 9Hz)

Production Example 18 The following compound was obtained in the same manner as in Production Example 16. 3- [4-
[2- (3-cyano-1-ethyl-5-methyl) pyrrolyl] benzyl-5,7-dimethyl-2- (2,2,2-
Trifluoro) ethoxy-3H-imidazo [4,5-
b] Pyridine mp: 144-147 ° C NMR (CDCl ₃ , δ): 1.14 (3H, t, J = 7.5Hz), 2.26 (3H, s),
2.50 (3H, s), 2.59 (3H, s), 3.81 (2H, q, J = 7.5Hz), 4.95 (2
(H, q, J = 8Hz), 5.31 (2H, s), 6.19 (1H, s), 6.86 (1H, s), 7.
35 (2H, d, J = 9Hz), 7.46 (2H, d, J = 9Hz)

Production Example 19 The following compound was obtained in the same manner as in Production Example 16. 3- [4-
[2- (3-Cyano-1-ethyl-5-methyl) pyrrolyl] benzyl-5,7-dimethyl-2- (2-methoxyethoxy) -3H-imidazo [4,5-b] pyridine. mp: 129-138 ° C NMR (CDCl ₃ , δ): 1.16 (3H, t, J = 7.5Hz), 2.27 (3H, s),
2.51 (3H, s), 2.57 (3H, s), 3.39 (3H, s), 3,72-3.80 (2H,
m), 3.82 (2H, q, J = 7.5Hz), 4.67-4.76 (2H, m), 5.31 (2H,
s), 6.20 (1H, s), 6.81 (1H, s), 7.32 (2H, d, J = 8.5Hz), 7.
46 (2H, d, J = 8.5Hz)

Production Example 20 The following compound was obtained in the same manner as in Production Example 16. 3- [4-
[2- (3-Cyano-1-ethyl-5-methyl) pyrrolyl] benzyl] -5,7-dimethyl-2-isopropoxy-3H-imidazo [4,5-b] pyridine. mp: 158-159.5 ° C NMR (CDCl ₃ , δ): 1.14 (3H, t, J = 7.5Hz), 1.37 (3H, s),
1.40 (3H, s), 2.27 (3H, s), 2.50 (3H, s), 2.56 (3H, s), 3.
82 (2H, q, J = 7.5Hz), 5.26 (2H, s), 5.42 (1H, quint, J = 6.0H
z), 6.20 (1H, s), 6.80 (1H, s), 7.32 (2H, d, J = 8.5Hz), 7.
43 (2H, d, J = 8.5Hz)

Production Example 21 3-amino-2- [4- [2- (3-cyano-1-ethyl-5-methyl) pyrrolyl] benzyl] amino-4,6
-In a solution of dimethylpyridine (481 mg) in tetrahydrofuran (5 ml), while stirring, ethyl isothiocyanate (123 µl) and triethylamine (197 µl)
Was added at room temperature and the resulting solution was heated at 50 ° C. for 24 hours. After cooling, the solvent was removed under reduced pressure and the volatiles were distilled off azeotropically with toluene (twice) to give 2- [4-
[2- (3-Cyano-1-ethyl-5-methyl) pyrrolyl] benzyl] amino-4,6-dimethyl-3- (3-
Ethylthioureido) pyridine was obtained as a pale yellow viscous oil. NMR (CDCl ₃ , δ): 1.12 (3H, t, J = 7.5Hz), 1.21 (3H, t, J =
7.5Hz), 2.15 (3H, s), 2.30 (3H, s), 2.40 (3H, s), 3.62 (2
H, dq, J = 7.5 and 8Hz), 3.87 (2H, q, J = 7.5Hz), 4.70 (2H,
d, J = 6Hz), 5.16 (1H, br, t, J = 6Hz), 5.65 (1H, m), 6.20 (1
H, s), 6.42 (1H, s), 6.83 (1H, br, s), 7.33 (2H, d, J = 9Hz),
7.41 (2H, d, J = 9Hz)

Production Example 22 2- [4- [2- (3-cyano-1-ethyl-5-methyl) pyrrolyl] benzyl] amino-4,6-dimethyl-
A mixture of 3- (3-ethylthioureido) pyridine and iodomethane (250 μl) in acetonitrile (5 ml) was stirred at room temperature for 3.5 hours and then warmed at 50 ° C. for 4 hours. The mixture was diluted with ethyl acetate, washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the residue was washed with diisopropyl ether, and a mixed solvent of methanol and chloroform (3.
-5% (V / V) as an eluent and purified by flash chromatography to give 3- [4- [2- (3-cyano-
1-ethyl-5-methyl) pyrrolyl] benzyl] -5
7-dimethyl-2-ethylamino-imidazo [4,5-
b] Pyridine (458 mg) was obtained as a brown amorphous solid. NMR (CDCl ₃ , δ): 1.15 (3H, t, J = 7.5Hz), 1.20 (3H, t, J =
7.5Hz), 2.28 (3H, s), 2.53 (3H, s), 2.55 (3H, s), 3.56 (2
H, dq, J = 7.5 and 6Hz), 3.83 (2H, q, J = 7.5Hz), 3.90 (1H,
t, J = 6Hz), 5.30 (2H, s), 6.20 (1H, s), 6.77 (1H, s), 7.27
(2H, d, J = 9Hz), 7.37 (2H, d, J = 9Hz)

Example 1 3- [4- (4-chloro-2-cyano-1-pyrrolyl)] benzyl] -2-ethylthio-7-methyl-3H
-1,3-Imidazo [4,5-b] pyridine (846 mg)
To a mixture in dimethyl-2-imidazolidinone (10 ml) was added sodium azide (539 mg) and triethylamine hydrochloride (1.425 g) and stirred at 135 ° C. for 24 hours. The reaction mixture is poured into ice-water and the pH is adjusted to 4 with 7% hydrochloric acid.
And extracted with ethyl acetate (twice), the separated organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue is crystallized from methyl cyanide,
After washing with hot methyl cyanide, 3- [4- (4-
Chloro-2- (1H-tetrazol-5-yl) -1-
Pyrrolyl] benzyl] -2-ethylthio-7-methyl-
3H-imidazo [4,5-b] pyridine (766 mg) was obtained as a brown solid. mp: 88-90 ° C NMR (DMSO-d ₆ , δ): 1.40 (3H, t, J = 7.5Hz), 2.56 (3H, s),
5.43 (2H, s), 6.90 (1H, d, J = 2Hz), 7.10 (1H, d, J = 5Hz), 7.
26 (4H, br, s), 7.48 (1H, d, J = 2Hz), 8.12 (1H, d, J = 5Hz)

Example 2 3- [4- [4-chloro-2- (1H-tetrazole-
5-yl) -1-pyrrolyl] benzyl] -2-ethylthio-7-methyl-3H-imidazo [4,5-b] pyridine (50 mg) is dissolved in aqueous sodium hydroxide solution (0.11 ml) and sonicated. Clarified by processing. This solution was filtered with a Millipore filter. The filtrate is lyophilized and
[4- [4-Chloro-2- (1H-tetrazole-5-
Yl) -1-pyrrolyl] benzyl] -2-ethylthio-
The sodium salt of 7-methyl-3H-imidazo [4,5-b] pyridine (51.6 mg) was obtained as a solid. NMR (D ₂ O, δ): 1.11 (3H, t, J = 7.5Hz), 2.42 (3H, s), 3.
04 (2H, q, J = 7.5Hz), 5.18 (2H, s), 6.31 (1H, d, J = 2Hz), 6.
52-6.65 (3H, m), 6.81-6.69 (3H, m), 7.90 (1H, d, J = 5Hz)

Example 3 3- [4- [4-Chloro-2- (1H-tetrazole-
To a stirred solution of 5-yl) -1-pyrrolyl] benzyl] -2-ethylthio-7-methyl-3H-imidazo [4,5-b] pyridine (700 mg) in dichloromethane (15 ml) was added m.
A solution of -chloroperbenzoic acid (670 mg; 80% pure) in dichloromethane (15 ml) was added dropwise below 5 ° C and the resulting mixture was stirred for 1.5 hours. Another solution of m-chloroperbenzoic acid (67 mg) in dichloromethane (5 ml) was added to the above mixture and stirring was continued for 1 hour. This mixture was washed with 1N hydrochloric acid and water. The aqueous layer was extracted with dichloromethane. The organic layers were combined and washed with water. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluted with dichloromethane-methanol (10: 1 then 8: 1 v / v)) to give 3- [4- [4-Chloro-2- (1H-tetrazol-5-yl) -1-pyrrolyl] benzyl] -2-ethylsulfonyl-7-methyl-
3H-imidazo [4,5-b] pyridine (210 mg) was obtained as an amorphous solid which was triturated with acetonitrile. NMR (DMSO-d ₆ , δ): 1.25 (3H, t, J = 7.5 Hz), 2.67 (3H,
s), 3.55 (2H, q, J = 7.5Hz), 5.86 (2H, s), 6.70 (1H, d, J = 2H
z), 7.20 (2H, d, J = 9Hz), 7.28 (2H, d, J = 9Hz), 7.33 (1H, d,
J = 2Hz), 7.38 (1H, d, J = 5Hz), 8.51 (1H, d, J = 5Hz)

Example 4 3- [4- [4-chloro-2- (1H-tetrazole-
5-yl) -1-pyrrolyl] benzyl] -2-ethylsulfonyl-7-methyl-3H-imidazo [4,5-b]
To a stirred solution of pyridine (209 mg) in ethanol (2 ml),
1N sodium ethoxide in ethanol solution (1.02m
l) and dichloromethane (30 ml) were added at room temperature, and the resulting mixture was heated under reflux for 2 hours. After cooling,
The mixture was treated with a 7% aqueous hydrochloric acid solution, and the separated organic layer was washed with water and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure and the residue was purified by preparative thin-layer chromatography (eluted with dichloromethane-methanol (8: 1 v / v)) to give 3- [4- [4-chloro-2 -(1H-tetrazol-5-yl) -1-pyrrolyl] benzyl] -2-ethoxy-7-methyl-3H-
Imidazo [4,5-b] pyridine (97 mg) was obtained as an amorphous solid which was triturated with diethyl ether. NMR (DMSO-d ₆ , δ): 1.40 (3H, t, J = 7.5 Hz), 2.46 (3H,
s), 4.60 (2H, q, J = 7.5Hz), 5.21 (2H, s), 6.49 (1H, d, J = 2H
z), 7.00 (1H, d, J = 5Hz), 7.10-7.26 (5H, m), 7.99 (1H, d,
(J = 5Hz)

Example 5 The following compounds were obtained in the same manner as in Example 2. 3- [4-
[4-Chloro-2- (1H-tetrazol-5-yl)
-1-pyrrolyl] benzyl] -2-ethoxy-7-methyl-3H-imidazo [4,5-b] pyridine sodium salt. NMR (D ₂ O, δ): 1.31 (3H, t, J = 7.5Hz), 2.33 (3H, s), 4.
40 (2H, q, J = 7.5Hz), 5.04 (2H, s), 6.47 (1H, d, J = 2Hz), 6.
59 (1H, d, J = 2Hz), 6.67 (2H, d, J = 8Hz), 6.81 (1H, d, J = 5H
z), 7.00 (2H, d, J = 8Hz), 7.79 (1H, d, J = 5Hz)

Example 6 3- [4- (2-bromo-4-cyano-1-methyl)]
To a stirred solution of -3H-imidazo [4,5-b] pyridine (1.30 g) in xylene (15 ml) was added trimethyltin azide (1.
72 g) were added at 125 ° C., stirred at the same temperature under a nitrogen atmosphere for 36 hours, and the solvent of the mixture was distilled off under reduced pressure. The residue was diluted with methanol and to this was added concentrated hydrochloric acid (1 ml). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was diluted with methanol and adjusted to pH 4 with 1N sodium hydroxide. The organic layer was separated and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel flash column chromatography (eluted with dichloromethane / methanol = 15/1) and preparative thin layer chromatography (dichloromethane / methanol =
(Eluted with 8/1) to give 3- [4- [2-bromo-
1-methyl-4- (1H-tetrazol-5-yl)-
2-Pyrrolyl] benzyl-2-ethylthio-7-methyl-3H-imidazo [4,5-b] pyridine (691 mg) was obtained as a colorless amorphous solid. NMR (DMSO-d ₆ , δ): 1.41 (3H, t, J = 7.5 Hz), 2.56 (3H,
s), 3.70 (3H, s), 5.38 (2H, s), 7.08 (1H, d, J = 5Hz), 7.20
(4H, br, s), 7.62 (1H, s), 8.13 (1H, d, J = 5Hz)

Example 7 3- [4- [2-Bromo-1-methyl-4- (1H-tetrazol-5-yl) -2-pyrrolyl] benzyl-2
-Ethylthio-7-methyl-3H-imidazo [4,5-
b] To pyridine (50 mg) was added a 1N aqueous solution of sodium hydroxide (0.10 ml) and water (1 ml) and the mixture was heated in a water bath. The solution was left at room temperature and the resulting solid was collected by filtration and diluted with ethanol. This solution was filtered with a Millipore filter. The solvent of the filtrate was distilled off under reduced pressure. The residue was dissolved in ethanol (0.2 ml) and water (2.5 ml) and lyophilized to give 3- [4
Sodium salt of-[2-bromo-1-methyl-4- (1H-tetrazol-5-yl) -2-pyrrolyl] benzyl-2-ethylthio-7-methyl-3H-imidazo [4,5-b] pyridine (42.6 mg) was obtained as a solid. NMR (DMSO-d ₆ , δ): 1.40 (3H, t, J = 7.5 Hz), 2.56 (3H,
s), 3.62 (3H, s), 5.34 (2H, s), 7.04-7.17 (3H, m), 7.19
(1H, s), 7.31 (2H, d, J = 9Hz), 8.12 (1H, d, J = 5Hz)

Example 8 3- [4- (3-cyano-1-ethyl-5-methyl-2)
-Pyrrolyl) benzyl] -2-ethylthio-7-methyl-3H-imidazo [4,5-b] pyridine (1.52 mg) in xylene (15 ml) was mixed with a mixture of trimethyltin azide (2.
26g) was added under a nitrogen atmosphere and stirred at 125 ° C for 24 hours. The mixture was concentrated under reduced pressure. Methanol and concentrated hydrochloric acid (1 ml) were added to the residue. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was diluted with methanol. The mixture was adjusted to pH 4 with 1N sodium hydroxide. The organic layer was separated and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (eluted with dichloromethane / methanol = 15/1), followed by crystallization with methyl cyanide to give 3- [4- [1-ethyl-5-methyl-3- ( 1H
An amorphous powder of (tetrazol-5-yl) -2-pyrrolyl] benzyl] -2-ethylthio-7-methyl-3H-imidazo [4,5-b] pyridine (1.47 g) was obtained. NMR (DMSO-d ₆ , δ): 1.01 (3H, t, J = 7.5Hz), 1.39 (3H, t,
J = 7.5Hz), 2.30 (3H, s), 2.57 (3H, s), 3.72 (2H, q, J = 7.5H
z), 5.44 (2H, s), 6.33 (1H, s), 7.11 (1H, d, J = 5Hz), 7.29
(4H, br, s), 8.14 (1H, d, J = 5Hz)

Example 9 The following compound was obtained in the same manner as in Example 2. 3- [4-
Sodium salt of [1-ethyl-5-methyl-3- (1H-tetrazol-5-yl) -2-pyrrolyl] benzyl] -2-ethylthio-7-methyl-3H-imidazo [4,5-b] pyridine . NMR (D ₂ O, δ): 0.71 (3H, t, J = 7.5 Hz), 1.15 (3H, t, J = 7.
5Hz), 2.16 (3H, s), 2.43 (3H, s), 3.09 (2H, q, J = 7.5Hz),
3.38 (2H, q, J = 7.5Hz), 5.34 (2H, s), 6.33 (1H, s), 6.89-
7.02 (3H, m), 7.08 (2H, d, J = 9Hz), 7.97 (1H, d, J = 5Hz)

Example 10 3- [4- [1-Ethyl-5-methyl-3- (1H-tetrazol-5-yl) -2-pyrrolyl] benzyl]-
2-ethylthio-7-methyl-3H-imidazo [4.5
-B] To a stirred solution of pyridine (661 mg) in dichloromethane (15 ml) was added m-chloroperbenzoic acid (778 mg; 80% pure) dropwise in an ice bath and the resulting mixture was added at the same temperature.
Stirred for hours. The ice bath was then removed and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with dichloromethane and the organic layer was washed with 10% aqueous sodium bisulfite, water and brine, dried over magnesium sulfate, then the organic layer was concentrated under reduced pressure and the residue was chromatographed on silica gel ( (Eluted with 7% (v / v) methanol-chloroform) to give a pale yellow solid. This material was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate to give crude 3- [4- [1
-Ethyl-5-methyl-3- (1H-tetrazole-5
-Yl) -2-pyrrolyl] benzyl] -2-ethyl-sulfonyl-7-methyl-3H-imidazo [4,5-b]
Pyridine (305 mg) was obtained, which was used for the next reaction without further purification.

Example 11 3- [4- [1-Ethyl-5-methyl-3- (1H-tetrazol-5-yl) -2-pyrrolyl] benzyl]-
2-ethylsulfonyl-7-methyl-3H-imidazo [4,5-b] pyridine (305 mg) and 1.0 M sodium ethoxide in 1.9 ml ethanol (3 ml).
And a mixture of dichloromethane (40 ml) was refluxed for 1.5 hours. An aqueous solution of hydrogen chloride was added to the reaction mixture until the pH of the solution became slightly acidic. The mixture was extracted with dichloromethane, washed with brine, dried over magnesium sulfate and chromatographed on silica gel (eluted with 5% methanol-chloroform) to give the desired compound (205 g) containing some impurities. Obtained. This was subjected to silica gel chromatography (eluted with methanol-acetic acid-ethyl acetate (1: 1: 18 v / v)) to give a compound also containing impurities (145 g). The mixture was subjected to thin layer chromatography for separation (twice), and then purified using chloroform-methanol-28% aqueous ammonia (130: 25: 5 v / v).
v), then ethyl acetate-methanol-acetic acid (1: 1:
38 v / v)), 2-ethoxy-3- [4- [1-
Ethyl-5-methyl-3- (1H-tetrazol-5
Yl) -2-pyrrolyl] benzyl] -7-methyl-3H
-Imidazo [4,5-b] pyridine (72 mg) was obtained. . Crystallization from diethyl ether and recrystallization from acetonitrile gave the pure compound (32 mg) as a white powder. mp: 192-196 ° C. NMR (DMSO-d ₆ , δ): 1.02 (3H, t, J = 7.5Hz), 1.39 (3H, t,
J = 7.5Hz), 2.29 (3H, s) 2.46 (3H, s), 3.73 (2H, q, J = 7.5H
z), 4.60 (2H, q, J = 7.5Hz), 5.28 (2H, s), 6.33 (1H, s), 7.
01 (1H, d, J = 5Hz), 7.30 (4H, s), 8.01 (1H, d, J = 5Hz)

Example 12 2-ethoxy-3- [4- [1-ethyl-5-methyl-
3- (1H-tetrazol-5-yl) -2-pyrrolyl] benzyl] -7-methyl-3H-imidazo [4,5
-B] 1 suspension of pyridine (32.0 mg) in water (1 ml)
N sodium hydroxide (72 μl) was added. The mixture was heated at 90 ° C. in a water bath, sonicated to clarify, and lyophilized to 2-ethoxy-3- [4- [1-ethyl-5.
-Methyl-3- (1H-tetrazol-5-yl) -2
The sodium salt of -pyrrolyl] benzyl] -7-methyl-3H-imidazo [4,5-b] pyridine (30 mg) was obtained as a white powder. NMR (DMSO-d ₆ , δ): 0.98 (3H, t, J = 7.5Hz), 1.40 (3H, t,
J = 7.5Hz), 2.24 (3H, s), 2.44 (3H, s), 3.68 (2H, q, J = 7.5H
z), 4.60 (2H, t, J = 7.5Hz), 5.73 (2H, s), 6.10 (1H, s), 7.
00 (1H, d, J = 5Hz), 7.18 (2H, d, J = 9Hz), 7.30 (2H, d, J = 9H
z), 8.00 (1H, d, J = 5Hz)

Example 13 Trimethyltin azide (716 mg) and 3- [4- [1-
(2-cyano-5-methyl) pyrrolyl] benzyl] -2
-Ethoxy-7-methyl-3H-imidazo [4,5-
b] A mixture of pyridine (430 mg) in xylene (5 ml) was added to 12
Stirred at 0 ° C. for 21 hours. After cooling, the mixture was diluted with ethanol (5 ml) and treated with 1N aqueous sodium hydroxide solution (3.5 ml) and stirred at room temperature for 0.5 h, then evaporated under reduced pressure. Residue is ethanol (5ml)
The solution was adjusted to pH 5 with 1N hydrochloric acid, the organic layer was separated and concentrated under reduced pressure. The residue was dissolved in 10% methanol-chloroform (50 ml), dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (3
% Chloroform, eluted with 10% methanol / chloroform), and then the combined fractions were crystallized from diethyl ether to give an initial yield of 2-ethoxy-7-methyl-3.
-[4- [1- (5-Methyl-2-1H-tetrazol-5-yl) -1-pyrrolyl] benzyl] -3H-imidazo [4,5-b] pyridine (152 mg) is a pale pink solid Was obtained as The filtrate was lyophilized with ether-water (1: 4) to give a second crop (265 mg). mp: 98-103 ° C NMR (DMSO-d ₆ , δ): 1.48 (3H, t, J = 7.5Hz), 1.99 (3H,
s), 2.48 (3H, s), 4.60 (2H, q, J = 7.5Hz), 5.29 (2H, s), 6.
18 (1H, d, J = 4Hz), 6.80 (1H, d, J = 4Hz), 7.01 (1H, d, J = 5H
z), 7.21 (2H, d, J = 9Hz), 7.31 (2H, d, J = 9Hz), 8.01 (1H, d,
(J = 5Hz)

Example 14 The following compounds were obtained in the same manner as in Example 2. 2-ethoxy-7-methyl-3- [4- [1- [5-methyl-2-
(1H-tetrazol-5-yl) pyrrolyl] benzyl] -3H-imidazo [4,5-b] pyridine sodium salt. NMR (D ₂ O, δ): 1.30 (3H, t, J = 7.5Hz), 1.73 (3H, s), 2.
31 (3H, s), 4.44 (2H, q, J = 7.5Hz), 5.10 (2H, s), 6.06 (1H,
d, J = 3Hz), 6.59 (1H, d, J = 3Hz), 6.80 (1H, d, J = 5Hz), 6.85
(2H, d, J = 9Hz), 7.11 (2H, d, J = 9Hz), 7.80 (1H, d, J = 5Hz)

Example 15 2-ethoxy-7-methyl-3- [4- [5-methyl-
2- (1H-tetrazol-5-yl) -1-pyrrolyl] benzyl] -3H-imidazo [4,5-b] pyridine (108 mg) in 3N hydrochloric acid (0.4 ml) and 1,4-dioxane (1.6 ml). Was stirred at 50 ° C. for 45 minutes. After cooling, the solvent was removed under reduced pressure and the remaining water was
Removed azeotropically with 4-dioxane. The residue was triturated in acetonitrile, and the resulting precipitate was collected by filtration and 2-hydroxy-3- [4- [5-methyl-2- (1H-tetrazol-5-yl) -pyrrolyl] benzyl] -7- Methyl-3H-imidazo [4,5-b] pyridine hydrochloride (87 m
g) was obtained as a light brown solid. mp: 168-174 ° C NMR (DMSO-d ₆ , δ): 2.00 (3H, s), 2.34 (3H, s), 5.10 (2
H, s), 6.16 (1H, d, J = 4Hz), 6.83 (1H, d, J = 4Hz), 6.91 (1H,
d, J = 5Hz), 7.20 (2H, d, J = 9Hz), 7.49 (2H, d, J = 9Hz), 7.86
(1H, d, J = 5Hz)

Example 16 Trimethyltin azide (284 mg) and 3- [4- [2-
(3-Cyano-1-ethyl-5-methyl) pyrrolyl] benzyl] -5,7-dimethyl-2-ethoxy-3H-imidazo [4,5-b] pyridine (114 mg) in xylene (3m
The mixture in l) was stirred at 125 ° C. for 16 hours. The reaction mixture was diluted with methanol (5 ml) and to this mixture was added 1N sodium hydroxide (about 2 mg). The mixture is at room temperature 30
Stir for minutes and then evaporate the solvent under reduced pressure. The residue was dissolved in methanol (5ml). The solution was adjusted to pH 4 with concentrated hydrochloric acid, the solvent was distilled off under reduced pressure, dried over magnesium sulfate, and the residue was purified by silica gel flash column chromatography (eluted with chloroform, then 3% methanol / chloroform). The solvent of the combined fractions was distilled off under reduced pressure and diethyl ether was added for crystallization. The resulting precipitate was collected by filtration and washed with methyl cyanide to give 5,7-dimethyl-2-ethoxy-3- [4- [1-ethyl-5-methyl-3- (1
H-tetrazol-5-yl) -2-pyrrolyl] benzyl] -3H-imidazo [4,5-b] pyridine (45 mg)
Was obtained as a pale pink solid. mp: 184-187 ° C NMR (DMSO-d ₆ , δ): 1.03 (3H, t, J = 7.5Hz), 1.36 (3H, t,
J = 7.5Hz), 2.29 (3H, s), 2.43 (3H, s), 2.46 (3H, s), 3.72
(2H, br, q, J = 7.5Hz), 4.56 (2H, q, J = 7.5Hz), 5.76 (2H, s),
6.33 (1H, s), 6.89 (1H, s), 7.25 (2H, d, J = 9Hz), 7.30 (2H,
(d, J = 9Hz)

Example 17 The following compounds were obtained in the same manner as in Example 12. 5,7-dimethyl-2-ethoxy-3- [4- [1-ethyl-5-
Methyl-3- (1H-tetrazol-5-yl) -2-
Pyrrolyl] benzyl] -3H-imidazo [4,5-b]
Sodium salt of pyridine. NMR (D ₂ O, δ): 0.63 (3H, br, t, J = 7.5Hz), 1.25 (3H, t,
J = 7.5Hz), 2.11 (3H, s), 2.20 (3H, s), 2.30 (3H, s), 3.32
(2H, m), 4.38 (2H, q, J = 7.5Hz), 5.11 (2H, s), 6.31 (1H, s),
6.51 (1H, s), 6.98 (2H, d, 9Hz), 7.15 (2H, d, J = 9Hz)

Example 18 The following compound was obtained in the same manner as in Example 16. 5,7-dimethyl-3- [4- [1-ethyl-5-methyl-3-
(1H-tetrazol-5-yl) -2-pyrrolyl] benzyl] -2-methoxy-3H-imidazo [4,5-
b] Pyridine. mp: 215-220 ° C NMR (DMSO-d ₆ , δ): 1.04 (3H, t, J = 7.5Hz), 2.29 (3H,
s), 2.44 (3H, s), 2.48 (3H, s), 3.71 (2H, q, J = 7.5Hz), 4.
14 (3H, s), 5.29 (2H, s), 6.35 (1H, s), 6.90 (1H, s), 7.26
(2H, d, J = 9Hz), 7.30 (2H, d, J = 9Hz)

Example 19 The following compounds were obtained in the same manner as in Example 16. 5,7-dimethyl-3- [4- [2- [1-ethyl-5-methyl-
3- (1H-tetrazol-5-yl)] pyrrolyl] benzyl] -2-propoxy-3H-imidazo [4,5-
b] Pyridine. NMR (CDCl ₃ -3drops CD ₃ OD): 0.99 (3H, t, J = 7.5Hz), 1.1
1 (3H, t, J = 7.5Hz), 1.35 (2H, m), 2.33 (3H, s), 2.54 (3H,
s), 2.55 (3H, s), 3.76 (2H, q, J = 7.5Hz), 4.53 (2H, t, J = 7.
5Hz), 5.35 (2H, s), 6.50 (1H, s), 6.87 (1H, s), 7.26 (2H,
d, J = 9Hz), 7.32 (2H, d, J = 9Hz)

Example 20 The following compounds were obtained in the same manner as in Example 12. 5,7-dimethyl-3- [4- [2- [1-ethyl-5-methyl-
3- (1H-tetrazol-5-yl)] pyrrolyl] benzyl] -2-propoxy-3H-imidazo [4,5-
b] The sodium salt of pyridine . mp: 162-166 ° C NMR (DMSO-d ₆ , δ): 0.89 (3H, t, J = 7.5Hz), 0.99 (3H, t,
J = 7.5Hz), 1.75 (2H, m), 2.24 (3H, s), 2.42 (3H, s), 2.48
(3H, s), 3.68 (2H, m), 4.46 (2H, t, J = 7.5Hz), 5.21 (2H, m
s), 6.10 (1H, s), 6.86 (1H, s), 7.15 (2H, d, J = 9Hz), 7.30
(1H, d, J = 9Hz)

Example 21 The following compounds were obtained in the same manner as in Example 16. 5,7-dimethyl-3- [4- [2- [1-ethyl-5-methyl-
3- (1H-Tetrazol-5-yl)] pyrrolyl] benzyl] -2- (2,2,2-trifluoro) ethoxy-3H-imidazo [4,5-b] pyridine. NMR (CD ₃ CD, δ): 1.11 (3H, t, J = 7.5Hz), 2.33 (3H, s),
2.52 (3H, s), 2.57 (3H, s), 3.70 (2H, q, J = 7.5Hz), 4.98 (2
(H, q, J = 8Hz), 5.86 (2H, s), 6.63 (1H, s), 6.89 (1H, s), 7.
30 (2H, d, J = 9Hz), 7.48 (2H, d, J = 9Hz)

Example 22 The following compound was obtained in the same manner as in Example 12. 5,7-dimethyl-3- [4- [2- [1-ethyl-5-methyl-
3- (1H-tetrazol-5-yl)] pyrrolyl] benzyl] -2- (2,2,2-trifluoro) ethoxy-3H-imidazo [4,5-b] pyridine sodium salt. mp: 162-172 ° C NMR (DMSO-d ₆ , δ): 0.99 (3H, t, J = 7.5Hz), 2.24 (3H,
s), 2.44 (3H, s), 2.52 (3H, s), 3.70 (2H, q, J = 7.5Hz), 5.
26 (2H, s), 5.28 (2H, q, J = 9Hz), 6.10 (1H, s), 6.96 (1H,
s), 7.19 (2H, d, J = 9Hz), 7.33 (2H, d, J = 9Hz)

Example 23 The following compounds were obtained in the same manner as in Example 16. 5,7-dimethyl-3- [4- [2- [1-ethyl-5-methyl-
3- (1H-Tetrazol-5-yl)] pyrrolyl] benzyl] -2- (2-methoxyethoxy) -3H-imidazo [4,5-b] pyridine. NMR (CDCl ₃ , δ): 1.12 (3H, t, J = 7.5Hz), 2.32 (3H, s),
2.53 (3H, s), 2.57 (3H, s), 3.31 (3H, s), 3,67-3.81 (4H,
m), 4.67-4.75 (2H, m), 5.32 (2H, s), 6.62 (1H, s), 6.83 (1
H, s), 7.26 (2H, d, J = 8.5Hz), 7.41 (2H, d, J = 8.5Hz)

Example 24 The following compounds were obtained in the same manner as in Example 12. 5,7-dimethyl-3- [4- [2- [1-ethyl-5-methyl-
3- (1H-tetrazol-5-yl)] pyrrolyl] benzyl] -2- (2-methoxyethoxy) -3H-imidazo [4,5-b] pyridine sodium salt. mp: 121-124 ° C NMR (DMSO-d ₆ , δ): 1.00 (3H, t, J = 7.5Hz), 2.24 (3H,
s), 2.42 (3H, s), 2.47 (3H, s), 3.28 (3H, s), 3.62-3.77
(4H, m), 4.61-4.69 (2H, m), 5.21 (2H, s), 6.11 (1H, s),
6.87 (1H, s), 7.20 (2H, d, J = 8.0Hz), 7.31 (2H, d, J = 8.0Hz)

Example 25 The following compounds were obtained in the same manner as in Example 16. 5,7-dimethyl-3- [4- [2- [1-ethyl-5-methyl-
3- (1H-tetrazol-5-yl)] pyrrolyl] benzyl] -2-isopropoxy-3H-imidazo [4
5-b] pyridine NMR (CDCl ₃ , δ): 1.10 (3H, t, J = 7.5 Hz), 1.42 (6H, d, J =
6.5Hz), 2.31 (3H, s), 2.52 (3H, s), 2.56 (3H, s), 3.71 (2
H, q, J = 7.5Hz), 5.27 (2H, s), 5.44 (1H, quint, J = 6.5Hz),
6.60 (1H, s), 6.81 (1H, s), 7.26 (2H, d, J = 8.5Hz), 7.41 (2
(H, d, J = 8.5Hz)

Example 26 The following compound was obtained in the same manner as in Example 12. 5,7-dimethyl-3- [4- [2- [1-ethyl-5-methyl-
3- (1H-tetrazol-5-yl)] pyrrolyl] benzyl] 2-isopropoxy-3H-imidazo [4,5
−b] pyridine sodium salt mp: 116-141 ° C. NMR (DMSO-d ₆ , δ): 0.99 (3H, t, J = 7.5 Hz), 1.36 (6H, d,
J = 6.0Hz), 2.25 (3H, s), 2.41 (3H, s), 2.49 (3H, s), 3.69
(2H, q, J = 7.5Hz), 5.19 (2H, s), 5.31 (1H, quint, J = 6.0H
z), 6.10 (1H, s), 6.86 (1H, s), 7.16 (2H, d, J = 8.0Hz), 7.
31 (2H, d, J = 8.0Hz)

Example 27 The following compounds were obtained in the same manner as in Example 16. 5-7-dimethyl-3- [4- [2- [1-ethyl-5-methyl-
3- (1H-tetrazol-5-yl)] pyrrolyl] benzyl] -2-ethylamino-3H-imidazo [4,5
-B] pyridine. mp: 237-243 ° C NMR (DMSO-d ₆ , δ): 1.03 (3H, t, J = 7.5Hz), 1.17 (3H, t,
J = 7.5Hz), 2.29 (3H, s), 2.36 (3H, s), 2.40 (3H, s), 3.24-
3.51 (2H, m), 3.72 (2H, q, J = 7.5Hz), 5.32 (2H, s), 6.34 (1
H, s), 6.70 (1H, s), 6.90 (1H, br, t, J = 5Hz), 7.19 (2H, d, J
= 9Hz), 7.29 (2H, d, J = 9Hz)

Example 28 The following compounds were obtained in the same manner as in Example 12. 5,7-dimethyl-3- [4- [2- [1-ethyl-5-methyl-
3- (1H-tetrazol-5-yl)] pyrrolyl] benzyl] -2-ethylamino-3H-imidazo [4,5
-B] pyridine. NMR (DMSO-d ₆ , δ): 0.98 (3H, t, J = 7.5Hz), 1.17 (3H, t,
J = 7.5Hz), 2.24 (3H, s), 2.36 (3H, s), 2.49 (3H, s), 3.26-
3.50 (2H, m), 3.70 (2H, q, J = 7.5Hz), 5.26 (2H, s), 6.09 (1
H, s), 6.68 (1H, s), 6.89 (1H, t, J = 6Hz), 7.08 (2H, d, J = 9H
z), 7.29 (2H, d, J = 9Hz)

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 43/00 116 A61P 43/00 116 (72) Inventor Takayuki Inoue 2-11-18-202 Takezono, Tsukuba, Ibaraki, Japan Inventor Yuki Sawada 1-602-208, Azuma, Tsukuba-shi, Ibaraki Pref. (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 471/04 107 A61K 31/435 A61K 31/44 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound of the formula: Wherein R ¹ is hydrogen, halogen, nitro, lower alkyl, lower alkoxy, amino or acylamino, R ² , R ³ and R ⁴ are each hydrogen, halogen, nitro, cyano, lower alkyl, lower alkenyl, lower alkylthio, Mono-, di- or trihalo (lower) alkyl, oxo (lower) alkyl, hydroxy (lower)
R ² and R ³ are linked together to form 1,3-butadienylene, R ⁵ is hydrogen or an imino protecting group, R ⁶ and R ⁷ are each hydrogen or Lower alkyl, R ⁸ is hydrogen or lower alkyl optionally having halogen or lower alkoxy, A is lower alkylene, Q is CH or N, X is N or CH, Y is NH, O or S, Z is NH , S, SO ₂ or O) and pharmaceutically acceptable salts thereof.